ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1

Menée à l'aide d'échantillons de carcinome hépatocellulaire d'origine humaine et de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel l'alpha-énolase 1, en dégradant l'ARN messager de la protéine régulatrice du fer IRP1, supprime la ferroptose des cellules cancéreuses

Résumé en anglais

α-Enolase 1 (ENO1) is a critical glycolytic enzyme whose aberrant expression drives the pathogenesis of various cancers. ENO1 has been indicated as having additional roles beyond its conventional metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we show that ENO1 suppresses iron regulatory protein 1 (IRP1) expression to regulate iron homeostasis and survival of hepatocellular carcinoma (HCC) cells. Mechanistically, we demonstrate that ENO1, as an RNA-binding protein, recruits CNOT6 to accelerate the messenger RNA decay of IRP1 in cancer cells, leading to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis. Moreover, through in vitro and in vivo experiments and clinical sample analysis, we identified IRP1 and Mfrn1 as tumor suppressors by inducing ferroptosis in HCC cells. Taken together, this study establishes an important role for the ENO1–IRP1–Mfrn1 pathway in the pathogenesis of HCC and reveals a previously unknown connection between this pathway and ferroptosis, suggesting a potential innovative cancer therapy.